Cis-isomers of n,n'-bis-(4-hydroxy-2,3,4,5-tetrahydrothiophene-3 - yl)-diamines and their salts having anti-inflammatory, antiulcer and as well activity

 

(57) Abstract:

The invention relates to CIS-isomers of N,N'-bis-(4-hydroxy-2,3,4,5-tetrahydrothiophene-3-yl)diamines of the formula I and their salts, where a-g, i-m R=H; a-C X= 0; and n=3; b n=4; n=5; n=6; d n=7; n=8; W n=9; h R=Ac, n=6; and n=6, and X = disuccinate; X = ditartrate; X l = diacetyltartaric; m X = 6-sulfoxylate dehydroabietic acid; n X = glycyrrhizinate; X = dichlorhydrate. The compounds possess anti-inflammatory, antiulcer and as well as activity. The compounds are non-toxic, derived from available raw materials and do not have side effects inherent in the known anti-inflammatory agents. 7 tab., 2 Il.

The invention relates to new chemical compounds, specifically to CIS-isomers of N,N'-bis-disubstituted amines and their salts.

The described compounds have a General formula

< / BR>
where a-g, i-m R=H; a-C X=0; and n = 3; b n = 4; n = 5; n = 6: n = 7; n = 8: W n = 9; h R = Ac, n = 6; and n = 6, and X = disuccinate; X = ditartrate; l X = diacetyltartaric; m X = 6-sulfoxylate dehydroabietic acid; n X = glycyrrhizinate; about X = dichlorhydrate,

and possess the biological activity.

This property suggests the possibility of using these soedineni diseases, as well as the imperfection of the known anti-inflammatory drugs, lies not so much in lack of efficiency, but in the existence of side effects almost all existing groups of compounds of this type were the incentive to search for new non-steroidal anti-inflammatory drugs (NSAIDs).

Known use as anti-inflammatory agents ortofena (voltaren, diclofenac-sodium), having the formula

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[1] has a strong Connection ulcerogenic effect.

The analysis of literature data shows that the synthesis and pharmacological testing of new chemical compounds that differ from existing NSAIDs capacity and selectivity of action, prolonged effect and no side effects, is an important task.

Effective courses of anti-inflammatory therapy is the search for means of stabilizing the lysosomal membrane [2], antioxidant [3] , as well as substances that have an inhibitory effect on antibody production of lymphoid and plasma cells [4] recently found that the correlation between anti-inflammatory activity of NSAIDs and risk of ulcer is oxygenase (COX), involved in PG biosynthesis. More ulcerogenic activity of NSAIDs have mainly inhibiting COX1and more anti - mainly inhibiting COX2. Currently active search for compounds specified action type. It is known that the number of cyclic sulfones detected compounds with high anti-inflammatory [5], and antiulcer activity and selectivity of action against COX1and COX2(drugs meloxicam [6] , benzocycloheptene [7] and others). A significant drawback of these drugs is a multi-stage synthesis and the use of expensive not readily available reagents.

The similar structure of these compounds of formula (I) is the substance

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described as a mixture of CIS - and TRANS-isomers, which have anti-inflammatory activity at a dose of 1/10 LD50- 700 mg/kg [8].

The objective of the invention is to expand the range of products that have anti-inflammatory activity, with improved properties.

This object is achieved with new chemical compounds of the aforesaid formula (I), which has expressed protivoop the Oia compounds is in the interaction of bisamine with 4-hydroxy-4,5-dihydrothiophene-1,1 - dioxide in ethanol, water or methanol at room temperature is given at the end of the description scheme.

According to the invention compounds (I) can also be obtained by reaction of 3-hydroxy-4-chloro-2,3,4,5 the tetrahydrothiophene - 1,1-dioxide with diamines in ethanol.

In both cases, with the release of 71-95% in terms of 3-hydroxy-4-chloro-2,3,4,5-tetrahydrothiophene-1,1-dioxide receive bigeminy in the form of a precipitate consisting of a mixture of CIS-(Ia-g) and TRANS-isomers (IIA-j). Isomeric composition was determined by the ratio of the squares of the signals of protons in acetate and nitrogen-containing substituents. According to PMR spectroscopy tetraazacyclooctane the content of CIS-isomers (Ia-g) in the mixture is 55-75%. A single recrystallization of the mixture of compounds (Ia-g), (IIA-g) from ethanol or aq. ethanol leads to an increase of the content in the sediment CIS-isomers (Ia-f) to 80-88%.

The subject invention are also water-soluble forms of the compounds, the corresponding salt of the formula (AI-o), which is obtained by treating compound (Iك) succinic, tartaric, salicylic, 6-sulfoderivatives or glycyrrhizic acid. For comparative evaluation of the activity of CIS - and TRANS-isomers of dihydrochloride disulphophenyl-diamine recip
The biological activity of the compounds of formula (I) as defined above, was studied by determining the toxicity, anti-inflammatory activity and antiulcer and antipyretic effect connection (Iك).

Acute toxicity of the compounds (Ia-a) was determined on outbred mice of both sexes in a single introduction into the stomach. The toxicity parameters were calculated by Litchfield and the Suggested method of probit analysis. LD50the new compounds are given in table. 1. As can be seen from the data table. 1, widely used in medicine anti-inflammatory substances, the toxicity of these compounds. All compounds belong to class IV moderately hazardous substances.

Anti-inflammatory action of the new compounds were studied on three models of inflammation, caused by a 0.1% solution of histamine, a 1% solution carragenine and 3% formalin solution under the aponeurosis of one of the hind paws of the mouse at a dose of 0.05 ml Of anti-inflammatory activity of the compounds was judged by the percentage increase in mass of inflamed paws as compared with healthy. Drug comparison served ortofen, taken at a dose of ED50. The results of the study are given in table. 2-4.

Research has shown that everything is connected to the rim of the base (Ia, b, g, W, o) whose activity exceeds the activity of voltaren in 2 times. CIS-isomers (Iك,o) twice more active than the corresponding TRANS-isomers (G,o).

In models of inflammation induced by injection of formalin, all of the compounds of formula (I) exhibit higher anti-inflammatory activity compared with the control (table. 3). The most activity on this model has a base (Iك), (Ia) and (Ia), and sulfoxylate dihydroabietic acid (Ei) and hydrochloride (A) all doses. The activity of TRANS-isomers - compounds (A) (at a dose of 25 mg/kg), base G) (at a dose of 50 mg/kg), as well as a mixture of CIS - and TRANS-isomers connection (In) (in a dose of 50 mg/kg) is lower than the activity voltaren (PL. 3).

All the compounds at a dose of 50 mg/kg significantly delay the development of inflammatory edema caused by Karenina. Most activity have the base (IB, d, e), as well as the dihydrochloride (O) (table. 4).

From the obtained data for the study of anti-inflammatory activity, it follows that for all models of inflammation, the compounds of formula (I) more effectively delay the development of inflammatory edema than known anti-inflammatory drug voltaren. On the model of histamine-induced edema activity R the ins-base actively hinder the development of inflammatory edema, than the corresponding stereoselectivity derivatives. CIS-isomers (I) significantly more active than the corresponding TRANS-isomers (II), and sum of CIS - and TRANS-isomers. If we talk about water-soluble form, the interest dihydrochloride (A) in the form of CIS-isomers. In addition, this compound is the most affordable from the point of view of the production technology, which is based on available original compounds.

In this regard, further investigation of the biological activity was performed for compound (A).

Antiulcer activity of dichlorhydrate CIS-N, N'-bis-(4-hydroxy-2,3,4,5-tetrahydrothiophene-1,1-dioxide-3-yl)-diamine (A) studied in outbred rats weighing 180-200 g at a dose of from 1/30 LD50. On the antiulcer activity was judged by impact on the degree of destruction of the gastric mucosa caused by ulcerogenic agents, acetylsalicylic acid and Cincotta, and by ligation of the pyloric part of the stomach by Shay [9].

The test results showed that dichlorhydrate CIS-N,N'-(4-hydroxy-2,3,4,5-tetrahydrothiophene-1,1-dioxide-3-yl)- diamine (A) unlike voltaren prevents destruction of the gastric mucosa, vocavi voltaren) (table. 5, 6). In ligation of the pyloric part of the stomach by Shay studied compounds reduces ulcerative lesions of the mucous membrane of the stomach 4 times compared with the control group animals (table. 7)

In experiments on rabbits and dogs were studied antipyretic action dichlorhydrate CIS-N, N'-bis-(4-hydroxy - 2,3,4,5-tetrahydrothiophene-1,1-dioxide-3-yl)-diamine (Io) against the background of increasing body temperature with the introduction of pyrogenal dose of 50 mg/kg intramuscularly (Fig. 1 and 2). It is established that in the first 3 hours after administration of the compound (O) was observed lowering of the body temperature of rabbits. By the fourth hour, the temperature was almost normal. In control group of animals temperature remained at a high level throughout the experiment (Fig. 1) (y-axis T is the temperature change of the body of animals; on the x-axis t - time temperature measurement, h).

In experiments on dogs found that by the third hour after the introduction of the junction temperature in the experimental group fell sharply, and by the 4th decreased to the initial level. In control group of animals, the temperature was decreased more slowly and by the 4th hour after the introduction of pyrogenal not fully normalized (Fig. 2).

Thus, the CIS-isomers of N,N ' have a pronounced anti-inflammatory action, not inferior to voltaren. For example, the most accessible and the most active compounds (A) shows that the compound exhibits antipyretic activity. Anti-inflammatory and antipyretic actions combined with antiulcer action unlike voltaren. In addition, compounds obtained fairly simple technological process, based on the available domestic raw materials of sulfolene.

This invention is illustrated in the examples.

Example 1. Obtain CIS-N,N'-bis-(4-hydroxy-2,3,4,5-tetrahydrothiophene-1,1-dioxide-3-yl)-trimethylenediamine (Ia). The solution 13,04 g (0,097 mol) 4-hydroxy-4,5-dihydrothiophene-1,1-dioxide and to 3.92 g (0,053 mol) of triethylenediamine in 70 ml of ethanol maintained at 20-25oC for 12 hours the precipitation is filtered off and dried, yielding 14,65 g (88%) of N,N'-bis-(4-sultanol-3-yl)trimethylenediamine in the form of a mixture of CIS- (65%) and TRANS- (35%) isomers. So pl. 190-193oC (aq. ethanol). Found, %: C 38,35; H 6,46; N 8,15; S 18,62. C11H22N2O6S2. Calculated, %: C 38,57; H To 6.43; N 8,19; S 18,71. To highlight the CIS isomer, the reaction mass was recrystallized successively from ethanol and aq. of ethanol. So pl. CIS-isomer 205-208oC (aq. ethanol). IR spectrum , cm-1: 1111, 1294 (SOoC for 12 hours the precipitation is filtered off and dried, yielding 14,94 g (96%) of N,N'-bis-(4-hydroxy-2,3,4,5-tetrahydrothiophene-1,1 - dioxide-3-yl)-tetramethylaniline in the form of a mixture of CIS- (60%) and TRANS-isomers. So pl. 193-196oC (aq. ethanol). To highlight the CIS isomer, the reaction mass was recrystallized successively twice from aq. of ethanol. So pl. CIS-isomer (IB) 208-210oC. Found, %: C 40,60; H Of 7.23; N 7,30; S 18,10. C12H24N2O6S2. Calculated, %: C 40,45; H Of 6.75; N 7,39; S 17,98. IR spectrum , cm-1: 1113, 1139, 1284, 1303 (SO2), 3122 (OH), 3278 (NH).

Example 3. Obtain CIS-N, N'-bis-(4-hydroxy-2,3,4,5 - tetrahydrothiophene-1,1-dioxide-3-yl)-pentamethylenebis (Ie). A solution of 4.83 g (being 0.036 mol) 4-hydroxy-4,5-dihydrothiophene-1,1 - dioxide and 2,04 g (0.02 mol) of pentamethylenebis in 45 ml of ethanol maintained at 20-25oC for 12 hours the precipitation is filtered off and dried, yielding of 5.45 g (82%) of N,N'-bis-(4 - hydroxy-2,3,4,5-tetrahydrothiophene-1,1-dioxide-3 - yl)pentamethylenebis in the form of a mixture of CIS- (75%) and TRANS-isomers. So pl. 138-145oC (aq. ethanol). To highlight the CIS isomer reaction mass paracrystal Geno, %: C 41,61; H 7,12; N 7,38; S 17,00; C13H26N2O6S2. Calculated, %: C 42,16; H 7,03; EUR 7.57 N; S 17,30. IR spectrum , cm-1: 1111, 1299 (SO2), 3105 (OH), 3289 (NH).

Example 4. Obtaining CIS - and TRANS - isomers of N,N'-bis-(4-hydroxy-2,3,4,5-tetrahydrothiophene-1,1-dioxide-3-yl)-diamine. a) a Solution of 13.4 g (0.1 mol) 4-hydroxy-4,5-dihydrothiophene-1,1-dioxide and 6.1 g (0.51 mol) hexamethylene-diamine in 100 ml of methanol maintained at 20-25oC for 6 h, the precipitation is filtered off and dried. Obtain 17.3 g (90%) of N, N'-bis-(4-hydroxy-2,3,4,5-tetrahydrothiophene-1,1-dioxide-3-yl)-hexamethylen-diamines in the form of a mixture of CIS- (Iك) (70%) and TRANS-isomers (G) [cf. 8]. So pl. 180-182oC. Found, %: C 43,55; H 7,22; N 7,27; S 16,70. C14H28N2O6S2. Calculated, %: C 43,75; H 7,29; N 7,29; S 16,67. The reaction mixture is boiled in 100 ml of acetonitrile, nerastvorim precipitate is filtered off, dried and recrystallized from methanol, isolated TRANS-isomer (II). The mother liquor is evaporated, recrystallized twice from aq. ethanol, pure CIS-isomer (I g). So pl. 198-200oC (aq. ethanol). IR spectrum , cm-1: 1105, 1130, 1289, 1311 (SO2), 3116 (OH), 3297 (NH). So pl. TRANS-isomer (II g) 163-168oC (from methanol). IR spectrum , cm-1: 1114, 1296 (SO2), 3084 (OH), 3248 (NH is on ethanol is added a solution of 6.1 g (0,053 mol) of the diamine in 90 ml of ethanol. The resulting solution was heated at 75oC for 1 h, cooled, solvent evaporated. The obtained viscous residue is dissolved in a minimum amount of water, adjusted the pH to 10 with concentrated aqueous ammonia solution. Precipitated by cooling the solution, the precipitate is filtered off and dried, yielding 8,51 g (44%) of a mixture of CIS - and TRANS-isomers of N, N'-bis-(4-hydroxy-2,3,4,5-tetrahydrothiophene-1,1-dioxide-3-yl)-hexamethylendiamine (Iك) and (G). The water evaporated, the residue was incubated for 12 h at 20-25oC in a mixture of 60 ml of pyridine and 40 ml of acetic anhydride. The solvents are evaporated in vacuum, the reaction mass is dissolved in chloroform and washed with water. The chloroform evaporated, the residue chromatographic on a column of silica gel and additionally highlight of 2.75 g (10% in terms of 3-hydroxy-4-chloro-2,3,4,5 - tetrahydrothiophene-1,1-dioxide) mixture of CIS-(Z) and TRANS(Z) isomers of N,N'-diacetyl-N,N'-bis-(4-acetoxy-2,3,4,5 - tetrahydrothiophene-1,1-dioxide-3-yl)-diamine.

Example 5. Obtain CIS-N, N'-bis-(4-hydroxy-2,3,4,5 - tetrahydrothiophene-1,1-dioxide-3-yl)-heptamethylnonane (Ia). The solution 4,18 g (0,031 mol) 4-hydroxy-4,5-dihydrothiophene-1,1-dioxide and of 2.21 g (of 0.017 mol) of heptamethylnonane in 45 ml of ethanol maintained at 20-25oC for 12 hours-Vol-heptamethylnonane in the form of a mixture of CIS-(Ia) (75%) and TRANS-(D) isomers. So pl. 149-154oC (aq. ethanol). Found, %: C 45,15; H 7,45; N 7,12; S 16,40. C15H30N2O6S2. Calculated, %: C 45,23; H Rate Of 7.54; N? 7.04 Baby Mortality; S 16,08. The reaction mass is recrystallized from ethanol, emit 2.7 g of the CIS isomer (Ia), so pl. 162-164oC. IR spectrum , cm-1: 1106, 1292, 1316 (SO2), 3111 (OH), 3297 (NH).

Example 6. Obtain CIS-N,N'-bis-(4-hydroxy-2,3,4,5-tetrahydrothiophene-1,1 - dioxide-3-yl)-octanediamine (Ie). The solution 8,46 g (0,063 mol) 4-hydroxy-2-sulfolene and of 4.90 g (0,034 mol) of octamethylene incubated at 20-25oC for 12 hours the precipitation is filtered off and dried, yielding 11,04 g (90%) of N,N'-bis-(4-hydroxy-2,3,4,5-tetrahydrothiophene-1,1-dioxide-3-yl)-octanediamine in the form of a mixture of CIS- (75%) and TRANS-isomers. So pl. 155-160oC. Found, %: C 46,32; H Of 7.96; N 6,83; S 15,45. C16H32N2O6S2. Calculated, %: C 46,60; H To 7.77; N 6,80; S 15,53. The reaction mass is recrystallized from ethanol, then from aq. ethanol emit 7,7 CIS-isomer, so pl. 187-190oC (aq. ethanol). IR spectrum , cm-1: 1105, 1135, 1291, 1311 (SO2), 3111 (OH), 3297 (NH).

Example 7. Obtain CIS-N,N'-bis-((4-hydroxy - 2,3,4,5-tetrahydrothiophene-1,1-dioxide-3-yl)-monomethylaniline (If). A solution of 3.12 g (is 0.023 mol) 4-hydroxy-2-sulfolene and 2,05 g (0,013 mol) noname is 80%) of N,N'-bis-(4-hydroxy-2,3,4,5-tetrahydrothiophene-1,1-dioxide-3-yl)- monomethylaniline in the form of a mixture of CIS- (80%) and TRANS-isomers. So pl. 155-157oC. Found, %: C 47,72; H Of 8.27; N 6,52; S 14,95. C17H34N2O6S2. Calculated, %: C 47,88; H 7,98; N 6,57; S 15,02. The reaction mass is recrystallized from ethanol, then from aq. ethanol produce 2.5 g of the CIS isomer, so pl. 208-210oC (aq. ethanol). IR spectrum , cm-1: 1107, 1286, 1308 (SO2), 3121 (OH), 3297 (NH).

Example 8. Obtain CIS-N, N'-diacetyl-N,N'-bis-(4-acetoxy-2,3,4,5-tetrahydrothiophene-1,1-dioxide-3-yl)- diamine (Z). A solution of 1.92 g (0,005 mol) of CIS-N,N'-bis(4-hydroxy-2,3,4,5-tetrahydrothiophene-1,1-dioxide-3-yl)- diamine (Iك) in a mixture of 10 ml of pyridine and 10 ml of acetic anhydride was kept at 20-25oC for 12 h, the excess pyridine and acetic anhydride is evaporated under vacuum. The residue is recrystallized from a mixture of diethyl ether and dichloromethane. Get 2 g (72%) tetraazacyclododecane (Z). So pl. 203-205oC. Found, %: C 47,49; H 6,92; 5,00 N; S 11,75. C22H36N2O10S2. Calculated, %: C 47,83; H Of 6.52; N 5,07; S 11,59. IR spectrum, ,, cm-1: 1124, 1144, 1299, 1318 (SO2), 1647 (NCO), 1741 (OCO). The acetylation TRANS-Samara (G) in the described conditions are TRANS-N, N'-diacetyl-N, N'-bis-(4-acetoxy-2,3,4,5 - tetrahydrothiophene-1,1-dioxide-3-yl)-hexamethylenediamine were (Z), so pl. 70-75oC. IR spectrum , cm-1oC). Gain of 9.1 g of substance (A) in the form of an amorphous precipitate. So pl. 227-229oC (decomp.). Found, %; C 36,86; H Of 6.49; N 5,95; S 13,95; Cl 15,76. C14H30Cl2N2O6S2. Calculated, %: C Of 36.76; H 6,56; N 6,13; S 14,00; Cl 15,54. IR spectrum , cm-1: 1144, 1326 (SO2), 1560 (NH2+), 3240 (OH).

A similar technique of pure TRANS-base (D) get the TRANS-isomer of dichlorhydrate N,N'-bis-(4-hydroxy-2,3,4,5 - tetrahydrothiophene-1,1-dioxide-3-yl)-diamine (O), so pl. 68-72oC (hygroscopic). IR spectrum , cm-1: 1131, 1313 (SO2), 1585 (NH2+), 3309 of user. (OH).

Dissolve of 3.85 g (0.01 mol) of the reaction mixture (example 4A) CIS - and TRANS-N, N'-bis-(4-hydroxy-2,3,4,5-tetrahydrothiophene-1,1-dioxide-3-yl)-hexamethylendiamine in 40 ml of 1M aqueous solution of hydrochloric acid and evaporated to dryness. Obtain 4.5 g (yield quantitative) of a mixture of CIS - and TRANS - isomeric diclorhidrato N,N'-bis-(4-hydroxy-2,3,4,5 - tetrahydrothiophene-1,1-dioxide-3-yl)-diamine (IR), identical in so square and the IR spectrum with a known pattern [8].

Prima). To a solution of 0,425 g (0,0026 mol) of succinic acid in 40 ml of water are added 0,485 g (0,0013 mol) of the compound (Iك), heated to complete dissolution. The solvent is evaporated in vacuum at 50oC, the residue is washed with ethanol and dried in a vacuum oil pump at 80oC. Yield salts of 0.85 g (93%). Found, %: C 42,21; H 6,38; N 4.26 Deaths; S Of 10.25. C22H40N2O14S2. Calculated, %: C 42,58; H 6,45; N To 4.52; S 10,30. So pl. 166-172oC (decomp.). IR spectrum , cm-1: 1131, 1148, 1288, 1318 (SO2), 1559 (NH2+), 1629 (COO-), 1707 (COOH), 3311 (OH).

Example 11. Getting ditartrate CIS-N,N'-bis-(4-hydroxy-2,3,4,5-tetrahydrothiophene-1,1-dioxide-3-yl)- diamine (VBE). To a solution of 0.62 g (0,0041 mole) of tartaric acid in 50 ml of water is added 0,77 g (0.002 mol) of N, N'-bis-(4-hydroxy-2,3,4,5-tetrahydrothiophene-1,1-dioxide-3-yl)-diamine (Iك), heated to complete dissolution. The solution is evaporated in vacuum at 50oC to dryness, the residue is washed with ethanol and dried. Obtain 1.3 g (94%) ditartrate. Found, %: C 38,56; H 6,16; N 3,67; S 8,90. C22H40N2O18S2. Calculated, %: C 38,60; H Of 5.85; N, 4.09 To; S 9,36. So pl. 116-121oC. (decomp. ). IR spectrum , cm-1: 1126, 1309 (SO2), 1607 of user. (NH2+, COOH-), 1730 (CPPH), 3434 (OH).

Example 12. Obtaining bis-atsetilsalitsilata is acetylsalicylic acid in 50 ml of water are added 0,77 g (0.002 mol) of N,N'-bis-(4-hydroxy-2,3,4,5 - tetrahydrothiophene-1,1-dioxide-3-yl)-diamine (Iك), heat until dissolved. The solution is evaporated in vacuum at 50oC, the residue was washed with diethyl ether, dried in the vacuum of an oil pump at 50oC. Get to 1.21 g (81%) of salt. Found, %: C 52,23; H 6,04; N 3,72; S 8,40. C32H44N2O14S2. Calculated, %: C 51,61; H 5,91; N 3,76; S 8,60. So pl. 61-65oC. IR spectrum , cm-1: 1131, 1311 (SO2), 1555 (NH2+), 1629 (COO-), 1748 (CH3COO), 3424 (OH).

Example 13. Obtaining bis-(1-carboxy-1,4-dimethyl-7-isopropyl-1,2,3,4,4 a,9,10,

10A-octahydrophenanthrene-6-sulfoxylate) CIS-N, N'-bis-(4-hydroxy-2,3,4,5-tetrahydrothiophene-1,1-dioxide-3 - yl)-diamine (Ei). To a solution of 0,672 g (0.002 mol) of 1-carboxy-1,4-dimethyl-7-isopropyl-1,2,3,4,4 a, 9,10,10-octahydrophenanthrene - 6-sulfonic acids in 50 ml of water is added 0,384 g (0.001 mol) of CIS-N, N'-bis-(4-hydroxy-2,3,4,5-tetrahydrothiophene-1,1 - dioxide-3-yl)-diamine (Iك) and 30 ml of ethanol. The mixture is heated until complete dissolution. The solvent is evaporated to dryness in vacuum at 50oC, the formed amorphous substance is dried in a vacuum oil pump at 80oC for 2 h Gain of 1.05 g (99%) of salt. Found, %: C 55,17; H 7,58; N 2,32; S 10,70. C54H84N2O16S42H2O. Calculated, %: C 54,92; H 7,46; N 2,37; S 10,85. So pl. 205-210oC (decomp.

Example 14. Obtaining salts of N,N'-bis-(4-hydroxy-2,3,4,5-tetrahydrothiophene-1,1 - dioxide-3-yl)-diamine and glycyrrhizic acid (In). To a solution of 0,821 g (0.001 mol) glycyrrhizic acid (the content of the basic substance according to HPLC 92%) in 25 ml ethanol at 50oC is added a warm solution 0,384 g (0.001 mol) of CIS-N,N'-bis-(4-hydroxy-2,3,4,5-tetrahydrothiophene - 1,1-dioxide-3-yl)-diamine (Iك) in 35 ml of water, the mixture was stirred at 50-70oC for 2 h, the Solvents evaporated in vacuum at 50oC to dryness, the residue is dried in a vacuum oil pump 2 h at 50oC receive 1.2 g (99%) of salt. Found, %: N 2,17; S 5,35. C56H89N2O22S2. Calculated, %: N 2,32; S 5,31. So pl. 192-195 (in Russian)oC (decomp.). IR spectrum , cm-1: 1128, 1312 (SO2), 1620 of user. (NH2+, COO-), 3425 (OH).

Example 15. The influence of compounds on histamine-induced swelling was studied on white mice. The inflammation caused by the introduction under the plantar aponeurosis of the right hind paws of 0.05 ml of 0.1% solution of histamine. The compound was administered inside a 2 h before injection of histamine and after 3 and 6 h after injection of histamine. About anti-inflammatory activity was assessed by the change in weight of the legs of animals. The research results are summarized in table. 2.

Example 16.elk introduction under the plantar aponeurosis of the right hind paws of 0.05 ml of 3% formalin solution. The compounds were injected inside for 2 h before injection of formalin, just before the introduction and after 3 and 6 h after flogging impact. The research results are summarized in table. 3

Example 17. The influence of compounds on kareninoy swelling, studied on white mice. The inflammation caused by the introduction under the plantar aponeurosis of the right hind paws of 0.05 ml of 1% solution Karenina. Compounds were introduced inside 2 hours prior to the introduction of Karenina, after 3 and 6 h after injection. The research results are summarized in table. 4.

Example 18. Experimental ulcers caused by the introduction of acetylsalicylic acid in rats inside 150 mg/kg twice a day. The day before playback of the model rats were deprived of food. The target compound was injected inside 1 hour prior to the introduction of acetylsalicylic acid and 1 hour after him. Through the day the animals were opened, counted the number of ulcers and destruction of the gastric mucosa. The research results are summarized in table. 5.

Example 19. An experimental model of gastric ulcers caused by intraperitoneal injection of cinchophen at a dose of 300 mg/kg to rats. The day before playback model, animals were deprived of food. The target compound was administered orally in a dose of from 1/30 LD50immediately is rocki stomach. The research results are summarized in table. 6.

Example 20. The ligation of the pyloric part of the stomach by Shay [9] were carried out on outbred rats weighing 180-200 g Animals the day before operations were deprived of food. Before surgery, animals were narcoticyou with Nembutal at a dose of 40 mg/kg After resection of the abdominal cavity on the white line removed the stomach and applied to the pyloric part of the stomach for a few seconds clip of the Pian. The animals were placed in layers seams. The target compound was injected inside 1 hour before surgery and 4 hours after her dose of from 1/30 LD50. Treatment was continued for 30 days on one dose. After 30 days, animals were dissected and counted the number of destructions. The research results are summarized in table. 7.

Example 21. Anti-pyretic properties of the compound (O) was studied on 4 rabbits and 8 dogs, while increasing the animals ' body temperature during intramuscular injection of pyrogenal dose of 50 mg/kg Over 1 h after injection of pyrogenal animals body temperature increases by 1-1,5oC. the body Temperature of the animals was measured before the introduction of pyrogenal and every hour after injection. The target compound was administered 2 hours after the introduction of pyrogenal in a dose of from 1/30 LD50. Under the influence of the connection is lnyh animals (Fig. 1, 2).

Thus, the new compounds CIS-isomers of N, N'-bis-(4-hydroxy-2,3,4,5-tetrahydrothiophene-1,1-dioxide-3-yl)-diamines and their salts (Ia-a) have pharmacological advantages over known anti-inflammatory drug voltaren. For example, the most accessible and the most active compounds (A) shows that the compound exhibits antipyretic activity. Anti-inflammatory and antipyretic actions combined with antiulcer action unlike voltaren. In addition, compounds obtained fairly simple technological way of available domestic raw - sulfolene.

Sources of information

1. M. D. Mashkovsky. Medicines, Torching, Kharkov, 1998, T. 1, S. 198.

2. H. G. Vogel, V. Vogel, Drug Discovery and Evaluation, Springer Verlag, Heidelberg, 1996, 236 p.

3. A. C. Saratikov, Etc. Primep. The modern concept inflorescence action of NSAIDs. // Pharmacol. and toxicol., 1982, v. 45, No. 2, S. 133-138.

4. A. M. Cernoch. The inflammation. M.: Medicine, 1979, 448 S.

5. U.S. patent 5147893 from 15.09.1992,

6. Eur. Pat, Appl. EP. 863134 // C. A., 1998, v. 129, 202758w.

7. A. K. Aberg, G. E. Wright, J. L. Chew // C. A., 1998, v. 129, 298411b.

8. AC USSR 1018390, published in BI N 8, 1994

9. N. Shay, S. A. Komarov,tetrahydrothiophene-3-yl)-diamines and their salts, General formula I

< / BR>
where a-g, i-m R=H;

a-C X=0;

and n=3;

b n=4;

in n=5;

g n=6;

d n=7;

e n=8;

W n=9;

h R=Ac,

n=6;

and n=6,

for X = disuccinate;

for X = ditartrate;

X l = diacetyltartaric;

m X = 6-sulfoxylate dehydroabietic acid;

n X = glycyrrhizinate;

about X = dichlorhydrate,

has anti-inflammatory, antiulcer and as well as activity.

 

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